CN1307567A - 1,5 benzodiazepine derivatives - Google Patents

1,5 benzodiazepine derivatives Download PDF

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CN1307567A
CN1307567A CN99807986A CN99807986A CN1307567A CN 1307567 A CN1307567 A CN 1307567A CN 99807986 A CN99807986 A CN 99807986A CN 99807986 A CN99807986 A CN 99807986A CN 1307567 A CN1307567 A CN 1307567A
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benzodiazepine
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篠崎胜雄
米田智幸
村田正和
三浦直良
前田清人
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Zeria Pharmaceutical Co Ltd
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Abstract

1,5-Benzodiazepine derivatives represented by general formula (1) and drugs containing the same, wherein R<1> represents lower alkyl; R<2> and R<3> are the same or different and each represents hydrogen or lower alkyl; R<4> represents cyclohexyl or phenyl; and n is an integer of 1 to 3. These compounds are useful as remedies/preventives for diseases in which gastrin receptor and/or CCK-B receptor participate.

Description

1,5-benzodiazepine analog derivative
Technical field
The present invention relates to crucial benzodiazepine analog derivative in medical field.Specifically, the present invention relates to new 1,5-benzodiazepine analog derivative, it can resist gastrin-receptor and/or the CCK-B (acceptor of cholecystokinin-B), and relate to the medicine that is used to prevent and/or treat the disease that wherein above-mentioned acceptor participates in.
Background technology
Cholecystokinin (CCK) is at duodenum and jejunal mucous membrane produces and the intestinal hormones of release, and simultaneously known its has as stimulating pancreatic secretion, promoting the effect that gall-bladder shrinks and stimulates insulin secretion.In addition, known CCK also is present in pallium, hypothalamus and the hippocampus with high density, and has the retarding effect of ingesting, hypermnesia effect, anxiety effect etc.On the other hand, gastrin is the intestinal hormones that is produced and discharged by the G cell that is distributed in the stomach hole, and the known effect that it has for example stimulating acid secretion, the hole contraction of promotion stomach and stimulates gall-bladder to shrink.
These CCK have five identical C-end amino acids with gastrin, and all show its effect by acceptor.Cck receptor is divided into periphery CCK-As and maincenter CCK-Bs, and periphery CCK-As is distributed in pancreas, gall-bladder, the enteron aisle etc., and maincenter CCK-Bs is distributed in the brain.Gastrin-receptor and CCK-Bs demonstrate similar characteristic and have high homology in the receptors bind experiment, thereby they can be called " CCK-Bs/ gastrin-receptor ".This receptoroid can be used for treating and/or preventing stomach ulcer as the agonist compounds of gastrin-receptor or CCK-B acceptor, duodenal ulcer, gastritis, reflux oesophagitis, pancreatitis, Zuo Linge-Ai Lisen (Zollinger-Ellison) syndrome, hole G hyperplasia, the substrate mucosal hyperplasia, cholecystitis, gallstone colic, the wriggling disease, irritable bowel syndrome, the tumour of some type, feed disease (eating disorder), sick (hospitalitis) is in hospital, Phobias (panicdisorder), dysthymia disorders, schizophrenia, Parkinson, tardive dyskinesia, Tourette's syndrome, pharmacological dependence and de-addiction.They also are considered to have as the effect of sedation-analgesia inducing action and enhancing opioid drug inductive sedation-analgesia [" Japanese medicine association of science circular " (Bulletin of japanese Pharmacological Society), 106,171-180 (1995); " future drugs " (Drugs of the Future), 18,919-931 (1993); " U.S.'s physiology magazine " (American Journal ofPhysiology), 269, G628-G646 (1995); " U.S.'s physiology magazine ", 259, G184-G190 (1990); " European pharmacology magazine ", 261,257-263 (1994); " pharmacology trend " (Trends in Pharmaeological Science), 15,65-66 (1994)].
As gastrin receptor antagonist, proglumide has been acknowledged as a kind of stomach ulcer and treating gastritis medicine.Therefore yet proglumide is low to the avidity of gastrin-receptor or CCK-B acceptor, and a little less than its therapeutic action.In addition, there is report to claim some benzodiazepine analog derivative such as L-365718 (Divazepide, JP 61-63666 A) and L-365260 (JP 63-238069 A) to show CCK-A receptor antagonism and CCK-B receptor antagonism.In addition, the compound with strong CCK-B antagonistic action is disclosed and can suppresses the acid secretion (WO 94/438, and WO 95/18110) that pentagastrin stimulates.Yet these compounds are not entirely satisfactory to the organism administration time.Therefore, still do not provide gastrin-receptor or the CCK-B receptor antagonist that is fit to clinical application so far.
Can in digestive tube and central nervous system, effectively prevent and/or treat the disease that each acceptor wherein participates in respectively with gastrin-receptor or the strong bonded compound of CCK-B acceptor.Therefore extremely need this compounds.
Disclosure of the Invention
In this present situation, the inventor has carried out big quantity research for addressing the above problem.Consequently, discovery has 1 of ad hoc structure, 5-benzodiazepine analog derivative has strong gastrin-receptor and/or CCK-B receptor antagonism and obtains good sour secretion inhibition, be suitable as the medicine that prevents and/or treats the disease that described acceptor participates thus, and submitted patent application (PCT/JP97/04534) already to.The present invention has finished further research.Found that various 1 of the branched chain fatty acid bases that contain, 5-benzodiazepine analog derivative can also suppress the acid secretion that pentagastrin stimulates better in rat, and in screech owl short-leg beagle, suppress the acid secretion that pentagastrin stimulates with heidenhain's pouch (Heidenhain pouch), finish the present invention thus.
So, the invention provides 1 of following formula (1) representative, 5-benzodiazepine analog derivative: R wherein 1Represent low alkyl group, R 2And R 3Can be identical or different and represent hydrogen atom or low alkyl group, R 4Represent cyclohexyl or phenyl and n to represent 1 to 3 integer; Or its salt.
The present invention also provides a kind of and contains 1, and 5-benzodiazepine analog derivative (1) or its salt are as the medicine of effective constituent.
The present invention also provides a kind of pharmaceutical composition, wherein contains 1,5-benzodiazepine analog derivative (1) or its salt and pharmaceutically acceptable carrier.
The present invention also provides as 1 of medicine, 5-benzodiazepine analog derivative (1) or its salt.
The present invention further provides a kind of method for the treatment of the disease that gastrin-receptor and/or CCK-B acceptor participate, it comprises administration 1,5-benzodiazepine analog derivative (1) or its salt.
The best mode that carries out an invention
Term used herein " rudimentary " is meant the straight or branched carbochain with 1-8 carbon number.
So, R in the formula (1) 1, R 2And R 3The low alkyl group example of expression can comprise methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, the 1-methyl butyl, the 2-methyl butyl, isopentyl, tert-pentyl, 1, the 2-dimethyl propyl, neo-pentyl, the 1-ethyl propyl, hexyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, isohexyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, 1-methyl isophthalic acid-ethyl propyl, 1-ethyl-2-methyl-propyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, heptyl, 1-methyl hexyl, 2-methyl hexyl, 3-methyl hexyl, 4-methyl hexyl, 5-methyl hexyl, the 1-ethyl pentyl group, the 2-ethyl pentyl group, the 3-ethyl pentyl group, 1-propyl group butyl, the 1-methylheptyl, the 2-methylheptyl, the 3-methylheptyl, the 4-methylheptyl, the 5-methylheptyl, the 6-methylheptyl, the 1-ethylhexyl, the 2-ethylhexyl, the 3-ethylhexyl, the 4-ethylhexyl, 1-propyl group amyl group, 2-propyl group amyl group, 3,3, the 4-tri-methyl-amyl, 3,4, the 4-tri-methyl-amyl, 1,1,2, the 2-tetramethyl butyl, 2,2,3, the 3-tetramethyl butyl, with 1,1,3, the 3-tetramethyl butyl.Wherein, preferred carbon number is 1 to 4 alkyl, special preferable methyl.
Especially preferred R wherein 1And R 2Be that methyl, n are 1 and R 3Be formula (1) compound of hydrogen atom, the just compound of following formula (1a):
Figure A9980798600071
R wherein 4Has above-mentioned identical implication.
The example of the salt of The compounds of this invention (1) is: with the acid salt of mineral acid formation, for example hydrochloride, vitriol, nitrate and hydriodate; With the acid salt of organic acid formation, for example mesylate and esilate; Inorganic salt, for example sodium salt, sylvite, calcium salt and magnesium salts; And organic salt, for example ammonium salt, pyridinium salt, triethylamine salt, ethanolamine salt, trans-4-Trans-4-Amino Cyclohexanol salt and N, N '-dibenzyl ethylenediamine salt.Wherein, special particular certain cancers, trans-4-Trans-4-Amino Cyclohexanol salt and N, N-dibenzyl ethylenediamine salt.
In the present invention, comprise all kinds of SOLVENTS thing of compound of the present invention (1) and compound (1), as its hydrate, and polymorphic form.In addition, also comprise all racemic modifications of The compounds of this invention (1), various diastereomer, non-enantiomer mixture and optically active substance.Wherein, preferred especially optically active substance.
Compound of the present invention (1) can be in view of the feature of its basic framework and group, prepare by using different synthetic methods.Some representative preparation methods will be described below.Preparation method A:
Figure A9980798600081
Wherein Boc represents tertbutyloxycarbonyl, and R 1, R 2, R 3, R 4Has above-mentioned identical implication with n.
Particularly, the reaction of tert-Butyl dicarbonate and 2-amino-3-benzyloxycarbonyl amino propionic acid obtains uncle 2--butoxy carbonyl amino-3-carbobenzoxy-(Cbz)-alanine, and the benzyl that goes down of its existence of carrying palladium and hydrogen at the catalyzer charcoal subsequently turns to the amino propionic acid of 3-amino-uncle 2--butoxy carbonyl.At alkali, under the existence as salt of wormwood, 2-fluoronitrobenzene and 3-amino-uncle 2--butoxy-carbonylamino propionic acid reaction obtains uncle 2--butoxy-carbonylamino-3-(2-nitrophenyl) alanine.With this product the catalyzer charcoal carry palladium in the presence of catalytic reduction, reflux in toluene obtains 2-oxo-uncle 3--butoxy carbonyl amino-1,3,4 thus subsequently, 5-tetrahydrochysene-2H-1,5-benzodiazepine .This compound and the reaction of 3-bromine tetrahydrobenzene obtain 2-oxo-uncle 3--butoxy carbonyl amino-5-(2-tetrahydrobenzene-1-yl)-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine .The catalyzer charcoal carry palladium or platinum oxide in the presence of this compound of hydrogenation obtain compound (A).On the other hand, oil of mirbane and catalyzer charcoal carry palladium or platinum oxide in the presence of hydrogenation 2-oxo-uncle 3--butoxy carbonyl-amino-5-(2-tetrahydrobenzene-1-yl)-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine obtains compound (B).When brooethyl tertiary butyl ketone and compound (A) or (B) at alkali; there is reaction down and handles deprotection with hydrochloric acid or similar substance subsequently as salt of wormwood; can obtain 1-tert-butyl carbonyl methyl-2-oxo-3-amino-5-cyclohexyl (or phenyl)-1; 3; 4; 5-tetrahydrochysene-2H-1,5-benzodiazepine .This compound by with triphosgene and 3-aminophenyl branched chain fatty acid at alkali, the existence reaction down as triethylamine can obtain compound of the present invention (1).Preparation method B
Figure A9980798600101
Wherein Boc, R 1, R 2, R 3, R 4Have and above-mentioned identical implication with n.
Specifically, compound (A) or compound (B) by with hydrochloric acid or similar substance reaction deprotection after, with triphosgene and 3-aminophenyl branched chain fatty acid at alkali, the existence reaction down as triethylamine obtains ureido derivatives thus.This ureido derivatives exists down and brooethyl tertiary butyl reactive ketone as salt of wormwood by at alkali, obtains compound of the present invention (1).
R wherein 3Be the compound (1) of low alkyl group, carrying out follow-up hydrolysis by the known method in this field with acid or alkali can be converted into wherein R with compound of the present invention (1) 3It is the The compounds of this invention (1) of hydrogen atom.
Zhi Bei compound (1) can be with free form or with the isolated in form of salt as mentioned above, and subsequent purificn.Separate and purifying carries out as extraction, concentrated, distillation, crystallization, filtration, recrystallization, grinding and chromatography by selecting suitable ordinary method.In addition, separate and the The compounds of this invention (1) of purifying can be converted into salt with acid or alkali with free form, this can also dissolve under heating in the known mode in affiliated field or similar processing is carried out subsequently by it is mixed with acid or alkali.And the chiral isomer of The compounds of this invention (1) can utilize suitable starting compound preparation.Also can be by conventional racemic split method preparation; for example by compound of the present invention (1) being converted into diastereomeric salt with conventional chiral acid; as dibenzoyl tartaric acid salt and subsequently diastereomeric salt is carried out optical resolution; or, separate and also carry out Ai Deman (Edman) degraded subsequently by being translated into non-mapping compound.
Compound of the present invention (1) or its salt can oral administration or parenterai administrations.As oral dosage form, compound of the present invention can be by suitably becoming solid pharmaceutical preparation such as tablet, powder and capsule with pharmaceutically acceptable carrier hybrid process, described pharmaceutically acceptable carrier for example is: vehicle, as lactose, mannitol, W-Gum and crystalline cellulose; Tackiness agent such as cellulose derivative, gum arabic and gelatin; Disintegrating agent such as calcium carboxymethylcellulose; And lubricant, as talcum powder and Magnesium Stearate.It also can form liquid pharmaceutical formulation, as liquid preparation, suspension and emulsion.
As the formulation of parenterai administration, it can form the injection liquid preparation, as passing through it is mixed with water, ethanol, glycerine etc.
Effective treatment of The compounds of this invention (1) or its salt or prevent the dosage of above-mentioned disease to change according to pharmaceutical dosage form, route of administration, age and illness.But usually, adult's a day oral dosage is 1 to 1000mg, and preferred 5 to 500mg.As medication, preferred administration every day 1 time or divide about 2 or 3 parts of administrations every day.
Because compound of the present invention (1) or its salt have hereinafter described strong gastrin-receptor and/or CCK-B receptor antagonism and good sour secretion inhibition, it is applicable to treatment, the disease of improving and/or preventing gastrin-receptor and/or CCK-B acceptor to participate, for example stomach ulcer, duodenal ulcer, gastritis, reflux oesophagitis, pancreatitis, Zollinger Ellison syndrome, cavity G hyperplasia (vaculating G cell hyperplasia), the substrate mucosal hyperplasia, cholecystitis, gallstone colic, the wriggling disease, irritable bowel syndrome, the tumour of some type, the feed disease, it is sick to be in hospital, Phobias, dysthymia disorders, schizophrenia, Parkinson, tardive dyskinesia, Tourette's syndrome, pharmacological dependence and de-addiction; And can be used for inducing the sedation-analgesia effect and strengthen the effect of opioid drug inductive sedation-analgesia.
Embodiment
The present invention will describe in detail by embodiment hereinafter, be not limited only to embodiment but should understand the present invention.
Embodiment 1
(±)-2-[3-[3-(1-tert-butyl carbonyl-methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl) urea groups] phenyl]-preparation of 2 Methylpropionic acid
Figure A9980798600121
(step 1)
The preparation of (±)-uncle 2--butoxy carbonyl amino-3-benzyloxycarbonyl alanine
In the solution (100ml) of yellow soda ash (2.05g), add (±)-2-amino-3-benzyloxycarbonyl alanine (4.6g) [according to currently known methods (" chemicals is learned circular " (Chem.Pharm.Bull), 7,616 (1959) preparations].Add the solution of tert-Butyl dicarbonate (4.68g) in tetrahydrofuran (THF) (100ml) subsequently.Stir under the room temperature subsequently and spend the night.With ethyl acetate washing reaction mixture.By adding after 1N hydrochloric acid transfers to 3 with water layer pH, with this water layer of dichloromethane extraction.Organic layer desolventizes with anhydrous sodium sulfate drying and steaming under reduced pressure after this, obtains title compound (6.51g) thus. 1H-NMR(CDCl 3)δ：1.43(9H，s)，3.45-3.70(2H，m)，4.20-4.42(1H，m)，
5.08(2H，s)，5.50(1H，brs)，5.73(1H，brs)，7.32(5H，s)，
8.27 (1H, brs). (step 2)
The preparation of (±)-uncle 2--butoxy carbonyl amino-3-(2-nitrophenyl) alanine
(±)-uncle 2--butoxy carbonyl amino-3-benzyloxycarbonyl-alanine (1.06g) is dissolved in the methyl alcohol (50ml), adds 10% charcoal subsequently and carry palladium (100mg).Under room temperature and nitrogen atmosphere, the gained mixture was stirred 2 hours.Filter this reaction mixture and concentrated filtrate under reduced pressure, obtain thus (±)-3-amino-uncle 2--butoxy carbonyl amino-propionic acid (540mg).It is dissolved in the ethanol (50ml).Add salt of wormwood (365mg) and 2-fluoronitrobenzene (377mg) then, under refluxing, heated 3 hours afterwards.Decompression is concentrated reaction mixture down, adds entry in resistates, with ether washing gained mixture.By adding after 1N hydrochloric acid transfers to 3 with water layer pH, with this water layer of dichloromethane extraction.Organic layer desolventizes with anhydrous sodium sulfate drying and steaming under reduced pressure after this, obtains title compound (530mg) thus. 1H-NMR(CDCl 3)δ：1.44(9H，s)，3.60-3.95(2H，m)，4.50-4.70(1H，m)，
5.37(1H，brs)，6.67-6.73(1H，m)，6.96-7.03(1H，m)，7.43-
7.49(1H，m)，8.13-8.19(1H，m)，8.26(1H，brs)，11.50(1H，brs)。(step 3)
(±)-2-oxo-uncle 3--butoxy carbonyl amino-1,3,4,5-tetrahydrochysene-2H-1, the preparation of 5-benzodiazepine
(±)-uncle 2--butoxy carbonyl amino-3-(2-nitrophenyl)-alanine (325mg) is dissolved in the methyl alcohol (50ml), adds 10% charcoal then and carry palladium (50mg).Under room temperature and nitrogen atmosphere, the gained mixture was stirred 1 hour.Filter this reaction mixture and concentrated filtrate under reduced pressure, obtain (±)-uncle 2--butoxy carbonyl amino-3-(2-aminophenyl)-alanine thus.It is suspended in the toluene (30ml).This suspension was heated 3 hours under refluxing, remove with the Dean-Stark extractor simultaneously and anhydrate.Decompression is concentrated gained solution down.Resistates is by (chloroform: methyl alcohol=20: 1) behind the purifying, the crystallization of adding Di Iso Propyl Ether goes out the resistates of purifying at chromatography on the silicagel column.After this collect the gained crystallization by filtering, obtain title compound (210mg) thus.Yield: 76%.Fusing point: 185-187 ℃ 1H-NMR (CDCl 3) δ: 1.44 (9H, s), 3.39-3.47 (1H, m), 3.80-3.98 (2H, m),
4.4?4-4.55(1H，m)，5.73(1H，brs)，6.71-6.88(3H，m)，6.97-
7.03 (1H, m), 7.82 (1H, brs). (step 4)
(±)-2-oxo-uncle 3--butoxy carbonyl amino-5-(2-tetrahydrobenzene-1-yl)-1,3,4,5-tetrahydrochysene-2H-1, the preparation of 5-benzodiazepine
To (±)-2-oxo-uncle 3--butoxy carbonyl amino-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine (28.6g) adds sodium bicarbonate (17.3g) and 3-bromine tetrahydrobenzene (33.2g) at N in the solution in the dinethylformamide (50ml), stirred 1 hour down at 50 ℃ subsequently.Make reaction mixture.Add frozen water then, with this reaction mixture of dichloromethane extraction.Organic layer is with the salt water washing and use anhydrous sodium sulfate drying subsequently.Decompression is steamed down and is desolventized.In resistates, add Di Iso Propyl Ether so that crystallization.Collect the gained crystallization by filtering then.The crystallization washing with alcohol, dry afterwards, obtain title compound (30.1g) thus.Yield: 82%. 1H-NMR(CDCl 3)δ：1.41(9H，s)，1.55-2.08(6H，m)，3.23-3.37(1H，m)，
3.69-3.82(1H，m)，3.87-4.12(1H，m)，4.42-4.55(1H，m)，
5.47-5.54(1H，m)，5.62-6.01(2H，m)，6.90-6.99(2H，m)，
7.08-7.22 (2H, m), 7.47 (1H, brs). (step 5)
(±)-2-oxo-uncle 3--butoxy carbonyl amino-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1, the preparation of 5-benzodiazepine
To (±)-2-oxo-uncle 3--butoxy carbonyl amino-5-(2-tetrahydrobenzene-1-yl)-1,3,4,5-tetrahydrochysene-2H-1, add 10% charcoal in the solution of 5-benzodiazepines (4.5g) in ethanol (200ml) and carry palladium (1g), stirred 2 hours under room temperature and the nitrogen atmosphere subsequently.Filter this reaction mixture, decompression is concentrated filtrate down.This resistates of recrystallization in ethanol obtains title compound (3.35g) thus then.Yield: 74% fusing point: 207-208 ℃ 1H-NMR (CDCl 3) δ: 1.11-2.07 (19H, m), 3.15-3.27 (1H, m),
3.33(1H，dd)，3.68(1H，dd)，4.38-4.49(1H，m)，5.53(1H，d)，
6.91-6.96 (2H, m), 7.11-7.16 (2H, m), 7.45 (1H, brs). (step 6)
(±)-1-tert-butyl carbonyl methyl-2-oxo-uncle 3--butoxy carbonyl amino-5-cyclohexenyl-1,3,4,5-tetrahydrochysene-2H-1, the preparation of 5-benzodiazepine
To (±)-2-oxo-uncle 3--butoxy carbonyl amino-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1, add brooethyl tertiary butyl ketone (2g), salt of wormwood (1.55g), potassiumiodide (125mg) and bromination four (normal-butyl) ammonium (120mg) in the solution of 5-benzodiazepine (3.35g) in methyl-sulphoxide (30ml), stirred 1 hour under the room temperature subsequently.In reaction mixture impouring frozen water, use ethyl acetate extraction afterwards.With salt water washing organic layer, use anhydrous sodium sulfate drying then.Remove solvent under reduced pressure, (ethyl acetate: purifying normal hexane=1: 3) obtains title compound (2.3g) to resistates thus by silica gel chromatography.Fusing point: 155-156 ℃ 1H-NMR (CDCl 3) δ: 1.15-2.07 (28H, m), 3.13-3.24 (1H, m),
3.26(1H，dd)，3.61(1H，dd)，4.11(1H，d)，4.39-4.50(1H，m)，
5.17(1H，d)，5.57(1H，d)，6.92-7.03(2H，m)，7.12-7.20(2H，m)。(step 7)
(±)-1-tert-butyl carbonyl methyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1, the preparation of 5-benzodiazepine
To (±)-1-tert-butyl carbonyl methyl-2-oxo-uncle 3--butoxy carbonyl amino-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1 adds 4N hydrochloric acid-dioxane solutions (10ml) in the solution of 5-benzodiazepine (2.2g) in ethanol (10ml).Under 50 ℃, the gained mixture was stirred 30 minutes.Decompression is concentrated reaction mixture down, adds the saturated sodium bicarbonate aqueous solution neutralization in resistates.With dichloromethane extraction gained mixture.Anhydrous sodium sulfate drying is used in organic layer salt water washing afterwards.Decompression is steamed down and is desolventized, and adds the Di Iso Propyl Ether crystallization in resistates.Filter and collect the gained crystallization, obtain title compound (1.1g) thus.Fusing point: 124-125 ℃ 1H-NMR (CDCl 3) δ: 1.11-2.08 (21H, m), 3.12-3.27 (2H, m),
3.40(1H，dd)，3.53-3.62(1H，m)，4.01(1H，d)，5.29(1H，d)，
6.92-7.04 (2H, m), 7.15-7.19 (2H, m). (step 8)
(±)-1-(1-tert-butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl)-3-[3-(1-methyl isophthalic acid-methoxycarbonyl) ethylphenyl] urea
Under ice-cooled, in 2-(3-the aminophenyl)-solution of 2-methyl-methyl propionate (142mg) in anhydrous tetrahydro furan (50ml), add triphosgene (81.7mg).Subsequently, in 15 minutes, divide 5 equal portions, every equal portions 67 μ L to add triethylamine (335 μ L).Make the temperature of gained mixture be increased to room temperature, this mixture was stirred 5 minutes in this temperature.At ice-cooled (±)-1-tert-butyl carbonyl methyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1, the 5-benzodiazepine (250mg) of in this mixture, adding down.Make the temperature of the mixture that obtains thus rise to room temperature, stirred subsequently 1 hour.In reaction mixture, add entry, by filtering the crystallization of collecting precipitation.Crystallization is suspended in the methyl alcohol heating gained suspension.Make this suspension cooling and collect the gained crystallization, obtain title compound (250mg) thus by filtering.Yield: 62% 1H-NMR (DMSO-d 6) δ: 1.10-1.82 (24H, m), 1.94-2.05 (1H, m),
3.16-3.45(3H，m)，3.56(3H，s)，4.30-4.43(2H，m)，5.12(1H，d)，
6.52 (1H, d), 6.80-6.85 (1H, m), 6.98-7.35 (7H, m), 8.87 (1H, s). (step 9)
(±)-2-[3-[3-(1-tert-butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl) urea groups] phenyl]-preparation of 2 Methylpropionic acid
To (±)-1-(1-tert-butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl)-and 3-[3-(1-methyl isophthalic acid-methoxycarbonyl) ethylphenyl] urea (250mg) is water-tetrahydrofuran (THF) (1: 1, add a hydronium(ion) oxidation lithium (91mg) in solution 10ml), subsequently reflux 6 hours.Make the reaction mixture cooling.Add this reaction mixture of 1N hcl acidifying, use the ethyl acetate extraction reaction mixture.Organic layer is with the salt water washing and use anhydrous sodium sulfate drying.Decompression is steamed down and is desolventized, by purification by silica gel column chromatography resistates (chloroform: methyl alcohol=10: 1).The resistates of purifying Virahol recrystallization obtains title compound (128mg) thus thus.Fusing point: 215-216 ℃ (decomposition) 1H-NMR (DMSO-d 6) δ: 1.10-1.82 (24H, m), 1.94-2.05 (1H, m),
3.16-3.45(3H，m)，4.30-4.43(2H，m)，5.12(1H，d)，6.52(1H，d)，
6.84-6.88(1H，m)，6.98-7.39(7H，m)，8.85(1H，s)，
12.20(1H，brs).MS(FAB)m/z：563(MH +).
Embodiment 2
(R)-(-)-and 2-[3-[3-(1-tert-butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl) urea groups] phenyl]-preparation of 2 Methylpropionic acid
Figure A9980798600171
(step 1)
(R)-(-)-preparation of uncle 2--butoxy carbonyl amino-3-(2-nitrophenyl amino) propionic acid
At N, add (R)-(-)-uncle 2--butoxy carbonyl amino-3-amino-3-propionic acid (5g) and salt of wormwood (6.77g) to 2-fluoronitrobenzene (3.45g) in the solution in the dinethylformamide (60ml), stir down at 70 ℃ subsequently and spend the night.With the reaction mixture cooling, in the impouring frozen water, use ethyl acetate extraction subsequently.By adding after 1N hydrochloric acid transfers to 3 with water layer pH, use the ethyl acetate extraction water layer.Organic layer is with using anhydrous sodium sulfate drying after the salt water washing.Remove solvent subsequently under reduced pressure.In resistates, add the normal hexane crystallization.Filter and collect the gained crystallization, obtain title compound (7.9g) thus.Yield: 99%.Fusing point: 141-142 ℃ of (decomposition) [α] D 25(C=1.00, CHCl 3) :-145 ° (step 2)
(R)-(+)-and 2-oxo-uncle 3--butoxy carbonyl amino-1,3,4,5-tetrahydrochysene-2H-1, the preparation of 5-benzodiazepine
, in the solution of methyl alcohol (100ml), add the 1O% charcoal and carry palladium (1g) to (R)-(-)-uncle 2--butoxy carbonyl amino-3-(2-nitrophenyl amino)-propionic acid (7.6g).Then, under room temperature and nitrogen atmosphere, stirred 3 hours.Filter this reaction mixture and concentrated filtrate under reduced pressure, obtain (R)-uncle 2--butoxy carbonyl amino-3-(2-aminophenyl amino) propionic acid thus.It is dissolved in the toluene (100ml).This vlil is spent the night.Make reaction mixture cooling and under reduced pressure concentrated.Resistates passes through in (the ethyl acetate: normal hexane=1: 1) behind the purifying, obtain title compound (5.16g) of chromatography on the silicagel column.Yield: 80%.Fusing point: 158-160 ℃ of [α] D 25(C=1.01, CHCl 3) :+7.21 ° of optical purity: 98%ee (passing through liquid chromatogram measuring) (step 3)
(3R)-(-)-and 2-oxo-uncle 3--butoxy carbonyl amino-5-(2-tetrahydrobenzene-1-yl)-1,3,4,5-tetrahydrochysene-2H-1, the preparation of 5-benzodiazepine
To (R)-(+)-2-oxo-uncle 3--butoxy carbonyl amino-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine (6.08g) is at anhydrous N, add sodium bicarbonate (3.68g) and 3-bromine tetrahydrobenzene (7.06g) in the solution in the dinethylformamide (50ml), stirred 1 hour down at 50 ℃ subsequently.Reaction mixture.Add frozen water then, use ethyl acetate extraction.Organic layer is with the salt water washing and use anhydrous sodium sulfate drying subsequently.Decompression is steamed down and is desolventized.(ethyl acetate: purifying normal hexane=1: 3) obtains title compound (7.84g) thus by silica gel column chromatography.[α] D 25(C=1.00, CHCl 3) :-179 ° of (step 4)
(R)-(-)-and 2-oxo-uncle 3--butoxy carbonyl amino-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1, the preparation of 5-benzodiazepine
To (3R)-(-)-2-oxo-uncle 3--butoxy carbonyl amino-5-(2-tetrahydrobenzene-1-yl)-1,3,4,5-tetrahydrochysene-2H-1, the platinum oxide (200mg) of adding prereduction in the solution of 5-benzodiazepine in tetrahydrofuran (THF) (200ml).Under room temperature and the nitrogen atmosphere gained mixture was stirred 2 hours.Through the diatomite filtration reaction mixture, decompression is concentrated filtrate down.On silicagel column, pass through chromatography (ethyl acetate: purifying resistates normal hexane=1: 3).In this resistates, add Di Iso Propyl Ether so that crystallization.Filter and collect the gained crystallization, obtain title compound (5.16g) thus.Yield: 67%.[α] D 23(C=1.00, CHCl 3) :-184 ° of (step 5)
(R)-(-)-and 2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1, the preparation of 5-benzodiazepine
To (R)-(-)-2-oxo-uncle 3--butoxy carbonyl amino-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1 adds 4N hydrochloric acid-dioxane solutions (10ml) in the solution of 5-benzodiazepine (5.11g) in ethanol (15ml).Under 50 ℃, the gained mixture was stirred 1 hour.Decompression is concentrated down then to make the reaction mixture cooling.In resistates, add the saturated sodium bicarbonate aqueous solution neutralization.With chloroform extraction gained mixture.Organic layer is with the salt water washing and use anhydrous sodium sulfate drying.Decompression is steamed down and is desolventized, and washs remaining crystallization with Di Iso Propyl Ether, and subsequent filtration is collected the gained crystallization.This crystallization obtains title compound (2.1g) thus with the mixed solvent recrystallization of ethanol and diisopropyl ether.Fusing point: 180-182 ℃ 1H-NMR (CDCl 3) δ: 1.06-2.07 (12H, m), 3.17-3.32 (2H, m), 3.49-
3.62 (2H, m), 6.90-6.99 (2H, m), 7.09-7.18 (2H, m), 7.45 (1H, s) .[α] D 25(C=1.04, CHCl 3) :-163 °. optical purity: 99%ee or higher (passing through liquid chromatogram measuring) (step 6)
(R)-(-)-and 1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl)-3-[3-(1-methyl isophthalic acid-uncle-butoxy carbonyl) ethylphenyl] preparation of urea
Under ice-cooled, in 2-(3-the aminophenyl)-solution of the 2 Methylpropionic acid tert-butyl ester (1.88g) in anhydrous tetrahydro furan (100ml), add triphosgene (890mg).Then, in 15 minutes, divide 5 equal portions, every equal portions 690 μ L to add triethylamine (3.45mL).Make the temperature of gained mixture be increased to room temperature, this mixture was stirred 5 minutes in this temperature.At ice-cooled (R)-(-)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1, the 5-benzodiazepine (2.0g) of in this liquid mixture, adding down.Make the temperature of the mixture that obtains thus rise to room temperature, stirred subsequently 1 hour.Decompression concentrates this reaction mixture down.In resistates, add entry, use dichloromethane extraction.Organic layer is with the salt water washing and use anhydrous sodium sulfate drying.Decompression is subsequently steamed down and is desolventized.With acetonitrile recrystallization resistates, obtain title compound (2.64g) thus.Yield: 64% fusing point: 185-187 ℃ of [α] D 21(C=1.03, CHCl 3) :-159 ° of (step 7)
(R)-(-)-and 1-(1-tert-butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl)-3-[3-(1-methyl isophthalic acid-tert-butoxycarbonyl) ethylphenyl] preparation of urea
To (R)-(-)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl)-and 3-[3-(1-methyl isophthalic acid-uncle-butoxy carbonyl) ethylphenyl] urea (2.6g) adds brooethyl tertiary butyl ketone (1.34g), salt of wormwood (1.04g), potassiumiodide (62mg) and bromination tetra-n-butyl ammonium (73mg) in the solution of methyl-sulphoxide (50ml), and the gained mixture at room temperature stirred 2 hours.In reaction mixture, add frozen water, use ethyl acetate extraction subsequently.Organic layer is used anhydrous sodium sulfate drying after with the salt water washing.Decompression is steamed down and is desolventized, by purification by silica gel column chromatography resistates (ethyl acetate: normal hexane=1: 2), obtain title compound (2.8mg) thus.Productive rate: 90% fusing point: 159-161 ℃ of [α] D 21(C=1.2, CHCl 3) :-69 ° of (step 8)
(R)-(-)-and 2-[3-[3-(1-tert-butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl) urea groups] phenyl]-preparation of 2 Methylpropionic acid
To (R)-(-)-1-(1-tert-butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl)-and 3-[3-(1-methyl isophthalic acid-tert-butoxycarbonyl) ethylphenyl] add trifluoroacetic acid (10ml) in the solution of urea (2.6g) in methylene dichloride (10ml), at room temperature stirred subsequently 1 hour.Decompression is concentrated reaction mixture down, adds diisopropyl ether so that crystallization in resistates.Collect the gained crystallization by filtering, obtain title compound (960mg) thus.Fusing point: 139-144 ℃ of [α] D 23(C=1.03, CHCl 3) :-111 °
Embodiment 3
(R)-and 2-[3-[3-(1-tertiary butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl) urea groups] phenyl]-2 Methylpropionic acid is trans-preparation of 4-Trans-4-Amino Cyclohexanol salt
Figure A9980798600221
With (R)-(-)-2-[3-[3-(1-tertiary butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl) urea groups] phenyl]-2 Methylpropionic acid (42mg) is dissolved in the acetonitrile (0.5ml).Add the dissolving of trans-4-Trans-4-Amino Cyclohexanol (8mg) and postheating.The placement of gained mixture is spent the night, filter the crystallization and the drying of collecting precipitation, obtain title compound (39mg) thus.Productive rate: 77%.Fusing point: 180-182 ℃ 1H-NMR (DMSO-d 6) δ: 1.09-1.97 (22H, m), 1.17 (9H, s), 1.35 (6H, s),
2.63(1H，m)，3.18-3.42(5H，m)，4.34(2H，m)，5.11(1H，d)，
6.64(1H，d)，6.86-7.31(8H，m)，8.95(1H，s)。
Embodiment 4
(R)-and 2-[3-[3-(1-tertiary butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl) urea groups] phenyl]-2 Methylpropionic acid N, the preparation of N-dibenzyl ethylenediamine salt
Figure A9980798600222
With (R)-(-)-2-[3-[3-(1-tertiary butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepines-3-yl) urea groups] phenyl]-2 Methylpropionic acid (158mg) and N, N-dibenzyl-ethylenediamin (67mg) adds in the acetonitrile (2ml), the postheating dissolving.Place this reaction mixture.Filter the crystallization and the drying of collecting precipitation, obtain title compound (200mg) thus.Productive rate: 89% fusing point: 105-106 ℃ 1H-NMR (DMSO-d 6) δ: 1.17 (9H, s), 1.20-1.99 (10H, m), 1.40 (6H, s),
2.58(4H，s)，3.17-3.44(5H，m)，3.67(4H，s)，4.34-4.43(2H，m)，
5.12(1H，d)，6.53(1H，d)，6.87-7.37(18H，m)，8.87(1H，s).
Embodiment 5
(R)-and 2-[3-[3-(1-tertiary butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl) urea groups] phenyl]-preparation of 2 Methylpropionic acid sodium
Figure A9980798600231
To (R)-(-)-2-[3-[3-(1-tertiary butyl carbonyl methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl) urea groups] phenyl]-add 1N sodium hydroxide (1.79ml) in the solution of 2 Methylpropionic acid (960mg) in methyl alcohol (10ml).Concentrating under reduced pressure gained solution.Resistates is by HP-20 (" Diaion " produced by Mitsubishi chemical company), and water and methyl alcohol purifying gained resistates obtain title compound (900mg) thus. 1H-NMR(DMSO-d 6)δ：1.10-1.83(24H，m)，1.90-2.05(1H，m)，
3.15-3.50(3H，m)，4.34-4.43(2H，m)，5.09(1H，d)，6.85-
6.95(2H，m)，6.97-7.12(3H，m)，7.20-7.30(4H，m)，9.20(1H，s)。Embodiment 6
(R)-(-)-and 2-[3-[3-(1-tertiary butyl carbonyl methyl-2-oxo-5-phenyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl) urea groups] phenyl]-preparation of 2 Methylpropionic acid (step 1)
(3R)-(-)-and 2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydrochysene-2H-1, the preparation of 5-benzodiazepine
To (3R)-2-oxo-3-butoxy carbonyl amino-5-(2-tetrahydrobenzene-1-yl)-1,3,4,5-tetrahydrochysene-2H-1, adding oil of mirbane (22.16g) and 10% charcoal carry palladium (6g) in the solution of 5-benzodiazepine (12.87g) in dimethylbenzene (200ml), heat 1 hour 30 minutes under refluxing subsequently.Reaction mixture and subsequent filtration.Decompression is concentrated filtrate down.Resistates is dissolved in the ethanol (30ml), adds 4N hydrochloric acid-dioxane solutions (20ml), stirred 1 hour down at 50 ℃ then.After the reaction mixture cooling, also wash, obtain the hydrochloride of title compound thus with the 2-propyl alcohol by the crystallization of filtering collecting precipitation.This hydrochloride is dissolved in the mixing solutions of first alcohol and water under heating.After the reaction mixture cooling, in reaction mixture, add the saturated sodium bicarbonate aqueous solution neutralization.By filtering the crystallization of collecting precipitation, wash with water and subsequent drying, obtain title compound (5.55g) thus. 1H-NMR(DMSO-d 6)δ：1.83(2H，brs)，3.41-3.53(2H，m)，
3.89(1H，ABq)，6.62-6.68(2H，m)，6.74-6.81(1H，m)，7.08-
7.25 (6H, m), 9.87 (1H, s) .[α] D 23(C=1.00, DMSO) :-66.0 °. (step 2)
(R)-(-)-and 1-(2-oxo-5-phenyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl)-3-[3-(1-methyl isophthalic acid-tert-butoxycarbonyl) ethylphenyl] preparation of urea
Under ice-cooled, in 2-(3-the aminophenyl)-solution of the 2 Methylpropionic acid tert-butyl ester (941mg) in anhydrous tetrahydro furan (100ml), add triphosgene (445mg) and mixing.After this, in 15 minutes, divide 5 equal portions, every equal portions 0.364ml to add triethylamine (1.7ml).Make the temperature of gained mixture be increased to room temperature, this mixture was stirred 5 minutes in this temperature.At ice-cooled (R)-(-)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydrochysene-2H-1, the 5-benzodiazepine (1g) of in this liquid mixture, adding down.Make the temperature of the mixture that obtains thus rise to room temperature, stirred subsequently 1 hour.Decompression concentrates this reaction mixture down.In resistates, add entry, use ethyl acetate extraction then.Anhydrous sodium sulfate drying is used in organic layer salt water washing afterwards.Decompression is subsequently steamed down and is desolventized.In resistates, add acetonitrile and carry out crystallization, obtain title compound (850mg) thus.Fusing point: 166-168 ℃ (decomposition) 1H-NMR (CDCl 3) δ: 1.32 (9H, s), 1.50 (3H, s), 1.53 (3H, s),
3.74(1H，dd)，4.44(1H，dd)，4.97(1H，dt)，6.22(1H，d)，
6.72-6.98(4H，m)，7.14-7.33(8H，m)，7.67-7.71(1H，m)，
8.30 (1H, s), 8.43 (1H, s) .[α] D 21(C=1.00, CHCl 3) :-191 °. (step 3)
(R)-(-)-and 1-(1-tert-butyl carbonyl methyl-2-oxo-5-phenyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl)-3-[3-(1-methyl isophthalic acid-tert-butoxycarbonyl) ethylphenyl] preparation of urea
Under ice-cooled, with (R)-(-)-1-(2-oxo-5-phenyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl)-3-[3-(1-methyl isophthalic acid-tert-butoxycarbonyl) ethylphenyl] urea (800mg) joins 60% sodium hydride (75mg) in anhydrous N, in the solution in the dinethylformamide (20ml), stir after 1 hour, add chloromethyl tertiary butyl ketone (251mg), stirred subsequently 1 hour.Allow the temperature of gained mixture rise to room temperature, and under this temperature, this mixture was stirred 30 minutes.In reaction mixture, add frozen water, use ethyl acetate extraction subsequently.Also use anhydrous sodium sulfate drying with salt water washing organic layer, decompression is subsequently steamed down and is desolventized.(ethyl acetate: purifying resistates normal hexane=1: 2) obtains title compound (920mg) thus by chromatography on silicagel column.Productive rate: 97%. 1H-NMR(CDCl 3)δ：1.23(9H，s)，1.36(9H，s)，1.48(6H，s)，
3.65(1H，dd)，4.26(1H，dd)，4.39(1H，d)，4.90(1H，dt)，
5.14(1H，d)，6.77-6.89(4H，m)，6.95-7.00(1H，m)，7.10-
7.33 (10H, m) .[α] D 21(C=1.02, CHCl 3) :-108 °. (step 4)
(R)-(-)-and 2-[3-[3-(1-tertiary butyl carbonyl methyl-2-oxo-5-phenyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl) urea groups] phenyl]-preparation of 2 Methylpropionic acid
Concentrated hydrochloric acid (2ml) is added (R)-(-)-1-(1-tertiary butyl carbonyl methyl-2-oxo-5-phenyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -3-yl)-and 3-[3-(1-methyl isophthalic acid-tert-butoxycarbonyl) ethylphenyl] in the solution of urea (850mg) in acetone (10ml), stirred 1 hour down at 10 ℃ subsequently.Decompression concentrates this reaction mixture down, adds entry in the gained resistates.The mixture that obtains thus with ethyl acetate extraction.With using anhydrous sodium sulfate drying behind the salt water washing extract, decompression is subsequently steamed down and is desolventized.On silicagel column, pass through chromatography purification resistates (chloroform: methyl alcohol=10: 1), obtain title compound (760mg) thus.Productive rate: 98%. 1H-NMR(DMSO-d 6)δ：1.17(9H，s)，1.42(6H，s)，3.57(1H，dd)，
3.97-4.07(2H，m)，4.58(1H，dt)，4.79(1H，d)，5.12(1H，d)，
6.63(1H，d)，6.78-6.92(4H，m)，7.13-7.33(8H，m)，7.42(1H，s)，
8.94 (1H, s), 12.25 (1H, brs) .[α] D 25(C=1.01, CHCl 3) :-160 °. with reference to preparation embodiment 1
Preparation (the step 1) of 2-(3-aminophenyl)-2-methyl-methyl propionate
Under ice-cooled, in the solution of 3-nitrophenyl acetonitrile (2g) in methyl alcohol (50ml), blast hydrogen chloride gas until saturated.Under the room temperature this solution stirring after 1 hour, is added entry (0.4ml), postheating refluxed 1 hour, afterwards concentrating under reduced pressure.In the gained resistates, add the saturated sodium bicarbonate aqueous solution neutralization, use ethyl acetate extraction then.Organic layer is used anhydrous sodium sulfate drying after using the salt water washing, obtains 3-nitrophenyl methyl acetate (2.31g) thus 1H-NMR (CDCl 3) δ: 3.73 (3H, s), 3.75 (2H, s), 7.48-7.55 (1H, m),
7.61-7.65 (1H, m), 8.10-8.19 (2H, m). (step 2)
Under ice-cooled, in N, the drips of solution in the dinethylformamide (10ml) adds to 60% sodium hydride (1.04g) in anhydrous N, in the suspension in the dinethylformamide (50ml) with 3-nitrophenyl methyl acetate (2.3g), stir after 10 minutes, drip methyl iodide (1.62ml).The temperature of gained mixture rises to room temperature, and stirs this mixture 2 hours under this temperature.In reaction mixture, add entry, use ethyl acetate extraction then.Organic layer is with the salt water washing and use anhydrous sodium sulfate drying, removes solvent under reduced pressure.On silicagel column, pass through chromatography purification gained resistates (ethyl acetate: normal hexane=1: 5), obtain 2-(3-nitrophenyl)-2 Methylpropionic acid methyl esters (1.8g) thus. 1H-NMR(CDCl 3)δ：1.65(6H，s)，3.68(3H，s)，7.47-7.55(1H，m)，
7.65-7.70(1H，m)，8.10-8.15(1H，m)，8.22-8.25(1H，m)。(step 3)
In 2-(3-the nitrophenyl)-solution of 2 Methylpropionic acid methyl esters (1.8g) in methyl alcohol (50ml), add 10% charcoal and carry palladium (200mg), under room temperature and nitrogen atmosphere, stirred 2 hours subsequently.Filter reaction mixture, decompression is concentrated filtrate down.(ethyl acetate: purifying gained resistates normal hexane=1: 2) obtains 2-(3-aminophenyl)-2 Methylpropionic acid methyl esters (1.5g) thus by chromatography on silicagel column. 1H-NMR(CDCl 3)δ：1.54(6H，s)，3.65(3H，s)，3.70(2H，brs)，
6.54-6.59(1H，m)，6.63-6.67(1H，m)，6.70-6.75(1H，m)，7.11(1H，t)。With reference to preparation embodiment 2
Preparation (the step 1) of 2-(3-aminophenyl)-2 Methylpropionic acid tert-butyl ester
To 3-nitrophenyl acetate (2.9g) the trimethyl carbinol-tetrahydrofuran (THF) (1: 1,40ml) add two carbonic acid two (tert-butyl ester) in the solution in (5.24g) and 4-Dimethylamino pyridine (0.5g), stir until stopping bubbling under the room temperature.Decompression is concentrated reaction mixture down, adds ethyl acetate and be used for extraction in resistates.Use 10% aqueous citric acid solution, saturated sodium bicarbonate aqueous solution, water and salt water washing gained extracting solution successively, use anhydrous sodium sulfate drying subsequently.Decompression is steamed down and is desolventized, and obtains 3-nitrophenyl tert.-butyl acetate (3.8g) thus. 1H-NMR(CDCl 3)δ：1.46(9H，s)，3.65(3H，s)，7.47-7.54(1H，m)，
7.59-7.64 (1H, m), 8.11-8.17 (2H, m). (step 2)
Under ice-cooled, at N, the drips of solution in the dinethylformamide (10ml) adds to 60% sodium hydride (1.41g) in anhydrous N, in the suspension in the dinethylformamide (50ml) with 3-nitrophenyl tert.-butyl acetate (3.8g), stir after 10 minutes, drip methyl iodide (2.2ml).The temperature of gained mixture rises to room temperature, and stirs this mixture 2 hours in this temperature.In reaction mixture, add entry, use ethyl acetate extraction then.Anhydrous sodium sulfate drying is used in organic layer salt water washing afterwards, and decompression is steamed down and desolventized.On silicagel column, pass through chromatography purification resistates (ethyl acetate: normal hexane=1: 5), obtain 2-(3-nitrophenyl)-2 Methylpropionic acid tert-butyl ester (3.6g) thus. 1H-NMR(CDCl 3)δ：1.39(9H，s)，1.59(6H，s)，7.45-7.53(1H，m)
7.64-7.71(1H，m)，8.08-8.14(1H，m)，8.22-8.26(1H，m)。(step 3)
In 2-(3-the nitrophenyl)-solution of the 2 Methylpropionic acid tert-butyl ester (3.6g) in ethanol (100ml), add 10% charcoal and carry palladium (400mg), under room temperature and nitrogen atmosphere, stirred 2 hours subsequently.Filter reaction mixture, decompression is concentrated gained filtrate down.(ethyl acetate: purifying gained resistates normal hexane=1: 5) obtains 2-(3-aminophenyl)-2 Methylpropionic acid tert-butyl ester (2.87g) thus by chromatography on silicagel column. 1H-NMR(CDCl 3)δ：1.38(9H，s)，1.48(6H，s)，3.62(2H，brs)，
6.52-6.57 (1H, m), 6.65-6.68 (1H, m), 6.71-6.76 (1H, m), 7.09 (1H, t). the experiment of experiment 1＜CCK-B receptors bind 〉
Isolate pallium by the Hartley male guinea pig.With pallium and 50mMtris-HCl damping fluid (pH 7.4) after the amount homogenate with 50 times of these pallium weight, 50, under the 000g with centrifugal 10 minutes of this homogenate.Add the same damping fluid of equivalent also centrifugal repeatedly 2 times to the gained settling.With the settling that finally obtains 10mM HEPES damping fluid (pH6.5, after this be called " solvent ") homogenizing, contain magnesium chloride (5mM), EGTA (1mM), bacitracin (0.25mg/ml) and sodium-chlor (130mM) in this HEPES damping fluid, and this homogenate provides as acceptor sample.
As in conjunction with the experiment, with final concentration be 1.0nM (50 μ L) [ 3H] (protein content: 800 μ g/ pipe) (900 μ L) joins solvent, final concentration is in the CCK-B solution or test compound solution (50 μ L) of 1.0 μ M, subsequently 25 ℃ of reactions 2 hours down for CCK-B solution and acceptor sample.After reacting completely, by this reaction mixture of Wattman GF/B filter suction filtration, this filter is handled with 0.1%BSA in advance, and uses the ice-cold 50mM tris-HCl damping fluid (pH 7.4) of 3ml part to wash this filter 4 times at once.In this filter, add the ACS-II scintillator, after this filter is placed about 24 hours, by the radioactive concentration on the liquid scintillation counter measurement filter.Combination note under CCK-B (the 1 μ M) existence is made non-specific binding, and the while is done the specificity combination by the numerical value note that complete combination deducts the non-specific binding gained, and wherein said complete combination is to obtain with described solvent replaced C CK-B.By [ 3H] the specificity combination of CCK-B, the computerized compound in conjunction with suppressing constant (Ki value).The result is that the Ki pH-value determination pH of the compound of embodiment 2 is 0.74nM.The sour excretory of test 2＜in rat pentagastrin is stimulated suppresses experiment 〉
Adopt male Sprague-Dawley (SD) rat.Use etherization, to undergo surgery ligation pyloric antrum and lay the duodenum interpolation pipe and gastric fistula pipe (gastric fistrlatube) of each rat.After operation finishes, rat is placed in the Barmann cage.Inject 15 μ g/kg/hr pentagastrins continuously through the tail vein.With 0.5% carboxymethylcellulose sodium solution (below be called " solvent ") test compound is made into suspension.At the start injection pentagastrin after 1 hour, through duodenum interpolation pipe administration solvent or test compound.With the acidity of autotitrator measurement sampling gastric juice, the acidity of product and the amount note of gastric juice are made acid output.Based on the acid output in the 1st hour to the 4th hour after the test compound administration 3 hours, determine that with following formula acid discharges inhibiting rate.The result is when with the 0.3mg/kg administration, and the acid secretion inhibiting rate of the compound of embodiment 2 performance is 72.7%, and the compound of embodiment 5 is during with 0.1mg/kg and 0.3mg/kg administration, and the acid secretion inhibiting rate that shows is respectively 48.8% and 79.3%.
Figure A9980798600301
Test 3＜CCK-A receptors bind experiment 〉
Isolate pancreas by the Hartley male guinea pig.10mM PIPES damping fluid (pH 6.5, below are called " solvent ") homogenate together with 40 times of amounts of pancreas and pancreas weight.This solvent contains EGTA (1mM), magnesium chloride (30mM), bacitracin (0.02%), soybean trypsin (tripsin) inhibitor (0.02%) and sucrose (0.3M).After gauze filters, 50, under the 000g with centrifugal 10 minutes of this homogenate.The described solvent of adding and settling same amount is centrifugal subsequently in the gained settling.The described solvent that in thus obtained settling, adds 40 times of these sediment yields, and with the settling homogenizing.This homogenate provides as acceptor sample.
As in conjunction with the experiment, with final concentration be 0.2nM [ 3H] L-364718 (Divazepide) solution (50 μ L) and be subjected to sample body (protein content: 50 μ g/ pipe) (900 μ L) joins described solvent, final concentration is in the L-364718 solution or test compound solution (50 μ L) of 1 μ M, subsequently 25 ℃ of reactions 2 hours down.After reacting completely, by this reaction mixture of Wattman GF/B filter suction filtration, this filter uses 0.1%BSA (bovine serum albumin) to handle in advance, and uses the ice-cold 10mM PIPES damping fluid (pH 6.5) of 3ml part to wash this filter 3 times at once.On this filter, add the ACS-II scintillator, after this filter is placed about 24 hours, by the radioactive concentration on the liquid scintillation counter measurement filter.Combination note under L-364718 (the 1 μ M) existence is made non-specific binding, deduct the resulting numerical value note of non-specific binding by complete combination simultaneously and do the specificity combination, wherein said complete combination is with solvent replacement L-364718 acquisition.By [ 3H] the specificity combination of L-364718, the computerized compound in conjunction with suppressing constant (Ki value).The result is that the Ki value of embodiment 2 compound determination is 438nM.Test 4
＜sour excretory the inhibition test that in having the screech owl short-leg beagle of heidenhain's pouch, pentagastrin stimulated 〉
Employing is pre-formed the screech owl short-leg beagle of heidenhain's pouch.Intravenously is with the amount injection pentagastrin of 4 μ g/kg/hr continuously.Inject pentagastrin continuously after 3 hours in beginning, be filled in the gelatine capsule each test compound and oral administration.With the acidity of autotitrator measurement sampling gastric juice, the acidity of product and the amount note of gastric juice are made acid output.Suppose that the acid output in preceding 1 hour of the administration is 100%, the acid output in the 1st hour to the 4th hour 3 hours after the test compound administration is converted into per-cent (per-cent is discharged in acid).Discharge per-cent based on this acid, determine that with following formula inhibiting rate is discharged in the acid of each beagle.The sour inhibiting rate of this compound of mean value note work of inhibiting rate is discharged in acid.The acid secretion inhibiting rate that the compound of result embodiment 2 when with the dosed administration of 1mg/kg shows is 77.9%.
Figure A9980798600311
Pharmaceutical preparation embodiment 1
The compound 20g of embodiment 5
Lactose 315g
W-Gum 125g
Crystalline cellulose 25g
Said components is mixed into uniform mixture.Add 7.5% hydroxypropylcellulose (200ml) subsequently.The extrusion granulator machine (opening diameter of described sieve is 0.5mm) that sieve is equipped with in utilization is made granular debris with the gained block.At once this granular debris is made sphere and subsequent drying becomes granule by Marumerizer.Pharmaceutical preparation embodiment 2
The compound 20g of embodiment 2
Lactose 100g
W-Gum 36g
Crystalline cellulose 30g
Calcium carboxymethylcellulose 10g
Magnesium Stearate 4g
Said components is mixed into uniform mixture.On one-shot head (single-punch) tabletting machine, mixture is pressed into the tablet of 200mg/ sheet by the drift of diameter 7.5mm.Pharmaceutical preparation embodiment 3
The compound 100mg of embodiment 6
Sodium acetate 2mg
Acetate (transferring to pH 5.8) an amount of (q.s.)
Distilled water an amount of (q.s.)
Total amount 10ml/ bottle
According to above-mentioned prescription, prepare injection liquid with the known method in affiliated field.
Industrial applicibility
Compound of the present invention has strong gastrin-receptor and/or CCK-B receptor antagonism With strong sour secretion inhibition, simultaneous altitude safety. So they can be widely used in Medical field is used for the treatment of, improves and/or prevents gastrin-receptor and/or CCK-B acceptor ginseng With disease wherein, for example gastric ulcer, duodenal ulcer, gastritis, reflux oesophagitis, Pancreatitis, Zollinger-Ellison Syndrome, cavity G hyperplasia, substrate mucosal hyperplasia, The tumour of cholecystitis, biliary colic, enterocinesia disease, irritable bowel syndrome, some type, Feed disease, the disease of being in hospital, panic disorder, depression, schizophrenia, Parkinson's syndrome, Tardive dyskinesia, Tourette's syndrome, pharmacological dependence and de-addiction; And can be used for luring Lead the sedation-analgesia effect and strengthen the sedation-analgesia effect that opioid drug is induced.

Claims (11)

1. 1 shown in the formula (1), 5-benzodiazepine analog derivative or its salt:
Figure A9980798600021
R wherein 1Represent low alkyl group, R 2And R 3Can be identical or different and represent hydrogen atom or low alkyl group, R 4Represent cyclohexyl or phenyl, and n represents 1 to 3 integer.
2. 1 described in the claim 1,5-benzodiazepine derivative or its salt, wherein R 1And R 2Be methyl, R 3Be that hydrogen atom and n are 1.
3. contain 1 described in claim 1 or 2,5-benzodiazepine derivative or its salt are as the medicine of effective constituent.
4. gastrin-receptor and/or CCK-B receptor antagonist contain 1 described in claim 1 or 2, and 5-benzodiazepine derivative or its salt are as effective ingredient.
5. according to the medicine of claim 3, it is a kind of acid secretion inhibitors.
6. according to the medicine of claim 3, it be applicable to the feed disease, the preventive or the therapeutical agent of be in hospital disease, Phobias, dysthymia disorders, schizophrenia, Parkinson, tardive dyskinesia, Tourette's syndrome, pharmacological dependence, stomach ulcer, duodenal ulcer, gastritis, reflux oesophagitis or Zollinger Ellison syndrome.
7. contain 1 described in claim 1 or 2, the pharmaceutical composition of 5-benzodiazepine analog derivative or its salt and pharmaceutically acceptable carrier.
8. 1 described in the claim 1 or 2,5-benzodiazepine derivative or its salt are as the application of medicine.
9. the application described in the claim 8, wherein said medicine be used to take food disease, the disease of being in hospital, Phobias, dysthymia disorders, schizophrenia, Parkinson, tardive dyskinesia, Tourette's syndrome, pharmacological dependence, stomach ulcer, duodenal ulcer, gastritis, reflux oesophagitis or Zollinger Ellison syndrome.
10. method for the treatment of the disease that gastrin-receptor and/or CCK-B acceptor participate, this method comprises uses 1 described in claim 1 or 2,5-benzodiazepine derivative or its salt.
11. the methods of treatment described in the claim 10, wherein said disease is selected from: feed disease, be in hospital disease, Phobias, dysthymia disorders, schizophrenia, Parkinson, tardive dyskinesia, Tourette's syndrome, pharmacological dependence, stomach ulcer, duodenal ulcer, gastritis, reflux oesophagitis or Zollinger Ellison syndrome.
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